ABSTRACT The widespread use of antiretroviral therapy (ART) has markedly changed the course of HIV disease and increased life-expectancy. However, evidence suggests that higher incidence of age-related comorbidities than would otherwise be expected, including cardiovascular disease and cancer, are contributing to a growing burden of multimorbidity among HIV-infected individuals and early death even with virally-suppressive ART. Resources developed by the Clinical Cohort and Comorbidity Research Core over the past 20 years position us uniquely to support multidisciplinary research designed to improve our understanding of the evolving treatment, progression, comorbidities, and outcomes of HIV infection in the contemporary ART era. We enter this next 5-year cycle with a well-established clinical cohort, research platform, study recruitment and specimen collection service that will be enhanced to serve a growing number of local, national and international investigators and an expanding HIV clinical, epidemiological, behavioral, basic and translational scientific agenda. We are proposing aims that capitalize on our uniqueness, our comprehensive accumulation of patient data with broad clinical scope and extensive longitudinal follow-up linked to biologic specimens, and ready access to study participants that enable projects to move rapidly from concept proposal to publication. Aim 1: We will expand the UW HIV Information System, UW HIV Clinical Cohort, and novel web-based platforms to capture and validate new data necessary to frame, design, and successfully answer central questions in contemporary HIV medicine and address emerging research priorities over the next five years. Aim 2: We will facilitate high-impact clinical research that will advance prevention and treatment of HIV-associated cardiovascular, metabolic, neurologic, pulmonary, liver disease and cancer to improve outcomes among persons aging with HIV. We will promote HIV Comorbidity Research Collaborations with local experts and leadership by early-career investigators to identify future scientific directions and target outcome adjudication required to define the clinical course and consequences of HIV-associated comorbidity and the impact of multimorbidity on survival. Aim 3: We will support cutting-edge basic and translational HIV research investigating biologic mechanisms of comorbid disease, HIV pathogenesis, progression, and approaches to HIV cure by recruiting study participants, providing banked specimens, and procuring protocol-driven and expanded types of specimens that investigators need for their research. Services provided by the Core will strengthen and expand collaboration among local investigators, foster synergy with other Cores and Scientific Working Groups, link early-stage investigators with established HIV scientists across disciplines, and create ties with scientists at other CFARs and HIV research centers, including through our leadership of the CFAR Network of Integrated Clinical Systems, necessary to combat the global HIV epidemic. 3